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665
ORIGINAL ARTICLE
A randomised, controlled trial of once daily and multi-dose
daily gentamicin in young Kenyan infants
M English, S Mohammed, A Ross, S Ndirangu, G Kokwaro, F Shann, K Marsh
...............................................................................................................................
Arch Dis Child 2004;89:665–669. doi: 10.1136/adc.2003.032284
See end of article for
authors’ affiliations
.......................
Correspondence to:
Dr M English, CGMR-C,
KEMRI/Wellcome Trust
Research Laboratories, PO
Box 230, Kilifi, Kenya;
menglish@wtnairobi.
mimcom.net
Accepted 7 October 2003
.......................
I
Aims: To test the suitability of a simple once daily (OD) gentamicin regimen for use in young infants where
routine therapeutic drug monitoring is not possible.
Methods: In an open, randomised, controlled trial, infants with suspected severe sepsis admitted to a
Kenyan, rural district hospital received a novel, OD gentamicin regimen or routine multi-dose (MD)
regimens.
Results: A total of 297 infants (over 40% (7 days) were randomised per protocol; 292 contributed at
least some data for analysis of pharmacological endpoints. One hour after the first dose, 5% (7/136) and
28% (35/123) of infants in OD and MD arms respectively had plasma gentamicin concentrations ,4 mg/
ml (a surrogate of treatment inadequacy). Geometric mean gentamicin concentrations at this time were
9.0 mg/ml (95% CI 8.3 to 9.9) and 4.7 mg/ml (95% CI 4.2 to 5.3) respectively. By the fourth day, predose concentrations >2 mg/ml (a surrogate of potential treatment toxicity) were found in 6% (5/89) and
24% (21/86) of infants respectively. Mortality was similar in both groups and clinically insignificant,
although potential gentamicin induced renal toxicity was observed in ,2% infants.
Conclusions: A ‘‘two, four, six, eight’’ OD gentamicin regime, appropriate for premature infants and those
in the first days and weeks of life, seems a suitable, safe prescribing guide in resource poor settings.
n adult patients there has been a substantial shift in
clinical practice towards the use of gentamicin once daily
over the past decade.1 The empiric evidence underlying this
change in practice has been summarised in several metaanalyses2–4 and reviews.5 However, although recognised as a
problem,6 7 there are few comparable efficacy data on the use
of once daily gentamicin regimes in the neonatal and early
infant period despite its common use for empiric treatment of
severe infection in this age group. Until 2001 published data
were only available from 71 infants treated in the first week
of life8 with data on a further 41 infants of a least 2500 g in
weight reported recently.9 While these largely pharmacokinetic data10–13 tend to support once daily gentamicin use,
reinforcing the recent World Health Organisation (WHO)
endorsement of this approach,14 there is little practical
guidance on how such a regime might be operationalised in
resource poor settings. Yet gentamicin administration in the
newborn period is far from straightforward. Early studies
suggest dose adjustment on the basis of both gestation and
postnatal age,15–18 and use of a ‘‘loading dose’’ is recommended.19 Extrapolation of the results of detailed, developed
country pharmacokinetic studies to resource poor settings
may also be difficult. In one study where it is explicitly
reported, almost 20% of infants had dose adjustments made
during a study of once daily treatment as a result of drug
concentration results.11 In other studies it seems likely that
there were even higher rates of real time dose adjustment if
‘‘abnormal results’’ were acted on.13
For those practicing in resource poor settings the picture
therefore remains somewhat confused. In Kenya, current
guidelines advise a multi-dose gentamicin regime that takes
into account both the presence of prematurity and postnatal
age,20 while the new WHO guidelines refer only to infants
over 3 kg in weight and suggest dose adjustment for age less
than 1 week only.14 The practical problems faced when using
gentamicin in resource poor countries include an absence of
accurate gestational age assessment, the inability to assess
renal function biochemically, and the absence of therapeutic
drug monitoring. Furthermore, on wards where staff to
patient ratios are very low, it is often only practical to
administer drugs at fixed times in the day rather than at
individually optimal times. Since case fatality rates are high
among sick young infants, and as they may be at higher risk
of drug related toxicity, we have investigated the use of a
novel once daily regimen. We compared its performance,
using pharmacological outcome measures, to the current
multi-dose regimen used in Kenya, in a situation that closely
mimics operational conditions.
METHODS
The study was undertaken at Kilifi District Hospital on the
Kenyan Coast, the main government inpatient facility for a
drainage population of at least 200 000 people. Interventions
available for the inpatient management of sick infants
include oxygen, antibiotics, intravenous fluids (not parenteral nutrition), nasogastric feeding of expressed breast milk,
phototherapy, and exchange transfusion. During the period
of the study an incubator was not routinely available. Sick
infants are investigated according to a standard protocol with
a full blood count, blood culture, plasma electrolytes,
creatinine (Beckman Instruments, USA), and glucose with
bilirubin and lumbar puncture performed when appropriate.
Empiric management of suspected severe infection is with
gentamicin and one of benzylpenicillin, ampicillin, or
cloxacillin, the choice being at the discretion of the admitting
clinician. Drugs are given at four fixed times daily. Once daily
(OD) drugs are given routinely at 09 00, twice daily drugs at
09 00 and 21 00, and thrice daily drugs at 09 00, 15 00, and
21 00. Except in rare instances infusion pumps are unavailable. Gentamicin is therefore routinely given intramuscularly.
The once daily gentamicin regimen was designed to
accommodate the practicalities of our setting and to take
account of the following assumptions: (1) if rapid bacterial
killing is desirable, then a high initial dose with a high initial
Abbreviations: MD, multi-dose; OD, once daily
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666
English, Mohammed, Ross, et al
serum peak gentamicin concentration is required;21 (2) dose
adjustment is required in the first week of postnatal life; (3)
dose adjustment for prematurity and low weight for
gestational age infants is necessary;15 16 and (4) increased
trough (pre-dose) concentrations of gentamicin increase the
risk of toxicity. As gestational age determination from history
is unreliable and estimation from physical features is
impractical, weight was used as a proxy measure. Table 1
describes the trial regimens. It should be noted that all
children in the OD arm received a first dose of 8 mg/kg before
continuing routine treatment with an age and weight specific
dose. In practice the OD regimen meant that children
received gentamicin only once per calendar day, although
this meant children admitted at 01 00 or 23 00 would both
receive their second doses at 09 00 the following day, dose
intervals of 32 hours and 10 hours respectively, before
starting true 24 hour dosing.
Approval for the study was obtained from the national
Kenyan Ethical Committee and it ran from August 2000 to
April 2001. All children less than 3 months of age admitted to
the ward until January 2001 and less than 2 months of age
from February 2001 were screened for enrolment in the study
using a computerised questionnaire. In January 2001 on the
basis of local bacteriological surveillance data (J Berkley, unpublished), the local management guidelines were changed,
limiting the use of gentamicin as empiric treatment to infants
less than 2 months of age. Children were excluded if: weight
was ,1 kg, there was a primary diagnosis of tetanus,
gentamicin had been administered previously, there were
major life threatening congenital malformations, there was a
history of anuria for 24 hours, or the admission creatinine
was outside a defined acceptable range (table 1). The parents
of children who remained eligible were given information
about the study in their local language by a trained project
assistant and consent was sought for enrolment. Confirming
that consent had been obtained on the questionnaire
triggered computerised randomisation and regimen allocation. Thus concealment was ensured although the study was
not blinded.
Two batches of gentamicin, from different manufacturers,
were used in sequence during the trial and were supplied by a
pharmaceutical agency (Mission for Essential Drugs and
Supplies) used by government and other hospitals. Vials
containing 40 mg/ml of gentamicin as the sulphate were
used. Although not ideal for use in infants, this formulation
is the most commonly available in practice. Venous or
capillary blood samples (volume 0.5 ml) were taken from
enrolled infants one hour after the first dose22 (the 1 hour
sample), before the second dose in children receiving once a
day therapy (the day 1 sample), one hour after the morning
dose on the third day of therapy (the 72 hour sample), and
immediately before the morning dose on the fourth day of
Table 1
Regimen
therapy (the 96 hour sample). Serum was frozen and stored
and gentamicin assays were performed in batches using an
Abbott TDx FLx auto-analyser (Abbott Diagnostics, IL, USA).
Intra-assay quality control using high, medium, and low level
standards showed coefficients of variation of ,3.6%. A repeat
creatinine measurement was obtained from the 96 hour
sample. The parents of infants prescribed prolonged treatment were asked if further pre-dose samples on the eighth
day of therapy could be taken for gentamicin assay and
measurement of creatinine.
Sample size estimation and statistical analysis
The trial regimens were to be compared on the basis of two
main endpoints: the proportion having a serum gentamicin
concentration .4 mg/ml in the 1 hour sample and the
proportion of infants with a serum gentamicin concentration
>2 mg/ml in the 96 hour sample. In addition the proportion
of children with a serum gentamicin concentration .4 mg/ml
in the 72 hour sample and the proportion having a significant
increase in plasma creatinine at 96 hours were to be
estimated for each group. The latter was defined as an
increase by more than 50% in plasma creatinine from
baseline that also resulted in a value outside the pre-defined
acceptable range23 24 (table 1). The study was not designed to
compare differences in mortality. A total sample size of 306
infants, assuming a 40% loss rate by 96 hours (due to death
and discharge), was calculated to be sufficient to show a
difference of 30%15 versus 10% in the proportion with a high
96 hour concentration in the multi-dose and once daily
groups respectively, with power 90% and significance 5%.
This sample size would be more than sufficient to show a
difference in inadequate peak concentrations at 1 hour of
50%25 versus 25% in multi-dose and once daily groups
respectively with the same power and significance.
During the study all data were entered in Foxpro 2.1 and
other than the study registration and randomisation questionnaire (that was entered directly at admission) all data
were double entered and verified. Two tailed Fisher’s exact
tests and t tests were used when comparing group proportions or means respectively. Skewed continuous data were
log transformed where appropriate prior to analysis. The
possible effect of gentamicin batch differences on the
outcomes low peak concentrations at 1 and 72 hours and
high trough concentrations at 96 hours was assessed using
logistic regression with adjustment for dosage group, admission creatinine, regimen, and sex. Analyses were conducted
with STATA 6 (Stata Corporation, USA).
RESULTS
Within the study period 566 infants of an age appropriate for
the study were admitted to the hospital. Figure 1 illustrates
recruitment from this total population and progress of
Gentamicin dosing regimen and defined acceptable range for creatinine
Age
Once daily
(7 days*
Once daily
.7 days
Multi-dose
(7 days*
Multi-dose
.7 days
23 24
Upper limit for creatinine mmol/l
Age 0–2 days
Age 3–7 days
Age 8–14 days
Age 14+ days
Weight ,2.0 kg
Weight >2.0 kg
2 mg/kg (group A.1)
4 mg/kg (group C.1)
2.5 mg/kg bd (group A.2)
2.5 mg/kg bd (group C.2)
4 mg/kg (group B.1)
6 mg/kg (group D.1)
2.5 mg/kg bd (group B.2)
2.5 mg/kg tds (group D.2)
190
120
100
90
140
110
90
90
*On the eighth day of life it was recommended that dosage was stepped up where appropriate to the dose
indicated for an 8 day old infant using the regime allocated at randomisation.
All children in the once daily group received an initial dose of 8 mg/kg before continuing with routine dosing
adjusted for weight and age.
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RCT of once daily gentamicin
infants in the study. Among the 297 infants enrolled as per
protocol mortality was 13% although among those aged
(7 days mortality was 24%. Table 2 presents basic demographic indices, baseline laboratory results, and process
indices for the two groups. Five children were administered
an incorrect first dose and had no blood samples taken. On
three occasions (3 MD) the time to the 1 hour peak sample
was outside our planned optimal range22(45–240 minutes
after dose administration), while this occurred on 25
occasions (15 in OD group) for the 72 hour peak sample.
Restricting analyses to samples collected within the optimal
range did not make any clinical or statistical difference to the
results or their interpretation. An intention to treat analysis
including all available data is therefore presented. Five
gentamicin concentrations at 1 hour and one at 72 hours
were .10 mg/ml but low sample volume precluded exact
measurement. These data are included in comparisons of
proportions only.
Peak gentamicin concentrations 1 hour after the first dose
were significantly higher in the infants treated once daily
667
(table 3). Trough concentrations at 96 hours were lower in
the OD treated infants. This resulted in a considerable
difference in the proportions of children with a trough
concentration ,2 mg/l in the OD and MD groups, although
this difference disappeared if a more stringent criterion of an
acceptable trough concentration (,1 mg/l26) was used for the
OD group. The considerable between patient variability in
gentamicin concentrations during treatment is illustrated by
the broad range of measured peak concentrations at 1 hour
and at 72 hours (table 3). Some of this variability may be
explained by drug administration errors or variable absorption after intramuscular injection in small, sick infants.
Logistic regression analysis controlling for age/weight group
membership, admission creatinine, drug batch received, and
the allocated regimen confirmed the strong association of the
OD regime with an adequate gentamicin concentration at
1 hour (OR 7.2, 95% CI 2.6 to 19.8) and absence of an
increased trough concentration at 96 hours (OR 7.5, 95% CI
2.4 to 24.0). Drug batch was not associated with any
outcome. Only approximately 2% of infants sampled at
Figure 1 Trial profile. *Diagnosed six
hours after admission. Admission
creatinine result obtained late, met
exclusion criteria.
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668
English, Mohammed, Ross, et al
Table 2
Characteristics of children studied
Median age [IQR] (days)
Proportion (7 days
Mean weight [95% CI] (kg)
Proportion (1.5 kg
Proportion .1.5,2.0 kg
Mean admission creatinine [95% CI] (mmol/l)
Mean admission WBC [95% CI] (1000/mm3)
Mean admission Hb [95% CI] (g/l)
Median time to 1 hour, ‘‘first peak’’ sample
[90% range] (minutes)
Median time from previous dose to 72 hour
sample, ‘‘peak concentration’’ [90% range]
(minutes)
Median time from previous dose to 96 hour
sample, ‘‘trough concentration’’ [90% range]
(minutes)
Once daily regime (n = 155)
Multi-dose regimes (n = 142)
8 [4–30]*
76/155, 49%
3.0 [2.8 to 3.1]
6/155, 4%
18/155, 12%
61 [56 to 67]
12.5 [11.3 to 13.6]
139 [133 to 144]
65 [60–92]
13 [4–32]*
51/142, 36%
3.2 [3.0 to 3.3]
3/142, 2%
14/142, 10%
57 [52 to 63]
13.1 [11.9 to 14.2]
134 [128 to 140]
65 [60–85]
70 [60–95]
71 [60–90]
1419 [1383–1470]
710 [683–750]
*p = 0.06 with two tailed Wilcoxon rank sum test.
96 hours had any evidence of possible gentamicin associated
renal impairment (table 3). Amongst these three children the
maximum measured creatinine was 121 mmol/l. All survived
without clinically apparent renal dysfunction. In 22 cases
(seven aged (7 days) where children were receiving
gentamicin for longer than one week, parents consented to
repeat pre-dose specimens taken on the eighth day (11 OD,
11 MD). One child died; none had a creatinine on the eighth
day .60 mmol/l and none had a pre-dose gentamicin
concentration >2 mg/ml.
DISCUSSION
Gentamicin is cheap, widely available and probably a highly
effective antibiotic for treating serious infection in young
infants in developing countries.27 Recent international guidelines suggest it should be used once daily in this age group.14
We felt there was a need to provide operational level data to
support once daily dosing, if appropriate, to encourage
clinicians from resource poor countries with many years of
Table 3
experience with multi-dose gentamicin regimens to change
their practice. Producing convincing evidence of the efficacy
of once daily gentamicin in sick young infants is however
problematic. As is shown by our data, trials using clinically
secure endpoints such as mortality would need to be
extremely large, and enthusiasm for these is likely to be
small given the conclusions of recent meta-analyses in other
patient groups.2–4 Pharmacological indices are widely used to
guide gentamicin dosing where therapeutic drug monitoring
is available, but the link between these indices, clinical
efficacy, and toxicity are not clear-cut.28 This makes
pharmacological endpoints imperfect as surrogate markers.
However, a convincing case can be made for the need to have
safe, high peak gentamicin concentrations, particularly on
starting treatment to maximise bacterial killing, and there is
good reason to believe that absence of drug free periods
predisposes to toxicity.5 19 21 Our results, showing much
improved initial gentamicin concentrations (almost a doubling) and of a four-fold reduction in prevalence of raised
Response to treatment
Once daily regime
Died (95% CI)
21/155
14%
(9% to 20%)
1 hour peak gentamicin concentration ,4 mg/ml
7/136
(95% CI)
5%
(2% to 10%)
Geometric mean 1 hour peak gentamicin
9.0
concentration (¡1 SD) (mg/ml)
(5.3, 15.4)
‘‘72 hour’’ peak gentamicin concentration ,4 mg/ml 12/102
(95% CI)
12%
(6% to 20%)
Geometric mean ‘‘72 hour’’ peak gentamicin
6.2
concentration (¡1 SD) (mg/ml)
(2.8, 13.7)
‘‘96 hour’’ trough gentamicin concentration
5/89
>2 mg/ml in OD and MD groups (95% CI)
6%
(2% to 13%)
‘‘96 hour’’ trough gentamicin concentration
21/89
>1 mg/ml in OD group and >2 mg/ml MD group
24%
(95% CI)
(15% to 34%)
Geometric mean ‘‘96 hour’’ trough gentamicin
0.6
concentration (¡1 SD) (mg/ml)
(0.3, 1.3)
Proportion with possible gentamicin nephrotoxicity
1/89
(95% CI)
1%
(0% to 6%)
Mean fall in plasma creatinine (mmol/l) at ‘‘96 hours’’ 18
(95% CI)
(11 to 25)
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Multi-dose regimes
18/142
13%
(8% to 19%)
35/123
28%
(21% to 37%)
4.7
(2.5, 9.0)
18/97
19%
(11% to 28%)
5.5
(3.0, 9.8)
21/86
24%
(16% to 35%)
21/86
24%
(16% to 35%)
1.1
(0.7, 2.3)
2/85
2%
(0% to 8%)
11
(5 to 17)
p = 0.99
p,0.001
p,0.001
p = 0.24
p = 0.19
p = 0.001
p = 0.99
p,0.001
p = 0.6
p = 0.13
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RCT of once daily gentamicin
669
.....................
pre-dose gentamicin concentrations on the fourth day of
treatment, are therefore very encouraging. Even if one
accepts that lower trough concentrations are desirable with
OD regimens,26 the OD regimen performed as well as the MD
regimens.
It was our intention that any results from this trial could
immediately be generalised to similar settings in resource
poor countries. The study was performed on a government
ward with average bed occupancy of over 100%. We used
commonly available, though suboptimal drug formulations,
and did not change pragmatic fixed time dosing. In addition
we included high risk groups (ignored in current international guidelines14) in the study population, testing an OD
regimen that requires determination of age and weight
(rather than gestation) only to decide on dosage in the
newborn period. As 14% of the sick infants admitted during
the study period weighed less than 2 kg, the predominant
cause being prematurity (observation of the authors), and as
over 40% were aged (7 days we feel this level of complexity
is warranted even in a developing country setting. It is
therefore reassuring to know that, without the benefit of
routine therapeutic drug monitoring to individually tailor
treatment, the OD regimen performed well. There is also a
lack of good data on the risks of gentamicin toxicity in
resource poor countries. Once again our data are reassuring.
The risk of possible nephrotoxicity seems low, and the limited
data we collected on infants receiving prolonged therapy
tends to support this conclusion. However, it should be
remembered that approximately 2% of sick young infants
thought to require parenteral antibiotics were excluded from
the trial because of a grossly raised creatinine at admission
(including three randomised but then excluded). In a setting
unable to measure creatinine these children are likely to be at
higher risk of unwitting gentamicin toxicity.
We therefore conclude, judged by pharmacological surrogates for clinical outcomes and in comparison with traditional multi-dose regimens, that our ‘‘two, four, six, eight’’
OD regime is a suitable regimen for infants up to 60 days of
age when used as empiric, unmonitored therapy in resource
poor countries. Adoption of such a regime is likely to reduce
costs13 and importantly spare valuable nursing time.
Changing local or national guidelines should however be
accompanied by appropriate training. In this context it
should be remembered that doses recommended in once
daily regimes should not be given as an intravenous bolus.
Intramuscular dosing is the preferred route unless reliable
infusion devices are available. As even with a high initial
dose, gentamicin concentrations were only moderate, future
studies should consider the possibility of even higher dosing
with two or even three day administration intervals.
ACKNOWLEDGEMENTS
This study is published with the permission of the Director of
KEMRI. The authors would like to thank the nurses and project
assistants on Ward 1 of Kilifi District Hospital for their invaluable
help during the conduct of this study. Particular thanks are owed to
Tom Oluoch who designed the patient entry/randomisation programme. Mike English (050563) and Kevin Marsh (031342) are
supported through Wellcome Trust fellowships.
Authors’ affiliations
M English, S Mohammed, A Ross, K Marsh, Centre for Geographic
Medicine Research, Coast, KEMRI/Wellcome Trust Research
Laboratories, PO Box 230, Kilifi, Kenya
S Ndirangu, G Kokwaro, Wellcome Trust Research Laboratories,
Nairobi, Kenya
F Shann, Royal Children’s Hospital, Melbourne, Australia
Financial support for this study was provided by the Wellcome Trust (UK)
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A randomised, controlled trial of once daily and
multi-dose daily gentamicin in young Kenyan
infants
M English, S Mohammed, A Ross, S Ndirangu, G Kokwaro, F Shann and K
Marsh
Arch Dis Child 2004 89: 665-669
doi: 10.1136/adc.2003.032284
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